Transcriptional regulation of cell life and death decisions by p73

p73 is the second member to be identified within the p53 family and shares structure and functions with p53. P73 generates various isoforms, which include full-length transcriptionally active (TA) isoforms and amino-terminal transactivation domain-deficient (ΔN) isoforms. TA isoforms of p73 are considered to act as tumor suppressors, whereas the ∆N isoforms of p73 act functionally analogous to other oncoproteins by counteracting the tumor suppressive functions of p53 and TAp73. In contrast to the P53, which is frequently mutated in a variety of human cancers, P73 mutations are very rarely found. However, altered expression of p73 or expression of abnormal p73 splicing variants is frequently detected in different type of cancers. In some cancer cell lines overexpression of TAp73α confers resistance to anticancer chemotherapeutic agents.

In our interest to identify transcriptional activities and molecular mechanisms of p73 isoforms that influence drug-induced apoptosis, we found that TAp73α inhibits drug-induced apoptosis by inducing the expression of Hsp72, a cell survival protein, in small cell lung carcinoma cells. TAp73α can also prevent caspase-2-induced apoptosis via inhibiting its enzymatic activity. In contrast, TAp73β induces the expression of p57kip2, which holds tumor suppressor properties. The pro-apoptotic effects of the TAp73β isoform seem to partially depend on the induction of p57Kip2. We discovered that different p73 isoforms transactivate cell cycle and apoptosis regulating gene promoters with different capability in a cell type-specific manner. Furthermore, we identified a functional cooperation between p53 family members, in which transcriptional activity of a DBD mutated isoform of TAp73α depends on the p53 status of the cell to transactivate cell cycle regulating P21 gene promoter.

In conclusion, our findings help to understand the isoform-specific transcriptional activities of p73 that determines its pro- and anti-apoptotic effects, upon drug treatment. These findings are expected to help in the development of new strategies to target cancer efficiently based on the p73 isoform present in the tumour and based on the context of the cell.

List of scientific papers

I. Nyman U, Naveen Reddy Muppani, Zhivotovsky B, Joseph B. Hsp72 mediates TAp73α anti-apoptotic effects in small cell lung carcinoma cells. J Cell Mol Med. 2011 Aug; 15(8):1757-68.
https://doi.org/10.1111/j.1582-4934.2010.01166.x

II. Naveen Reddy Muppani, Nyman U, Joseph B. TAp73alpha protects small cell lung carcinoma cells from caspase-2-induced mitochondrial mediated apoptotic cell death. Oncotarget. 2011 Dec; 2(12):1145-54.
https://pubmed.ncbi.nlm.nih.gov/22201672

III. Ulrika Nyman, Pinelopi Vlachos, Naveen Reddy Muppani, and Bertrand Joseph. The p73β transcriptional target gene p57Kip2 promotes p73β-mediated mitochondrial apoptotic cell death. [Manuscript]

IV. Naveen Reddy Muppani, Ulrika Nyman, Bertrand Joseph. DNA binding domain independent transcriptional activity of p73 depends on the p53 status of the cell. [Manuscript]